The use of metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, has long been known for the treatment of trichomoniasis and more recently for the treatment of bacterial vaginosis. There are currently at least two effective ways to treat trichomoniasis or bacterial vaginosis with the administration of a metronidazole composition. In the first method, a single, large dose (.about.2 grams) of metronidazole is given as a bolus to the patient. The single treatment is clinically effective. A major drawback to the administration of a single large dose of metronidazole is occurrence of significant and undesirable side effects such as nausea.
A second and more generally accepted treatment entails orally administering 250 mgs of metronidazole three times a day for a period of 7 days. The lower dosages of metronidazole over a period of a week significantly reduce the occurrence and severity of side effects. However, patient compliance is a problem since patients can inadvertently forget to take one or more doses during the course of treatment, causing the plasma metronidazole levels to drop to below an acceptable therapeutic level for a period of several hours or more.
The use of metronidazole is also known for the treatment of various other conditions, including amebiasis (acute amebic dysentery), and Helicobacter pylori infections associated with duodenal ulcer disease, see, e.g., D. Graham, et al., Annals of Internal Medicine, 115, 266-269 (1991).
In order to reduce the number of daily doses of metronidazole needed to treat a microbial infection, while maintaining the benefits of making bioavailable effective amounts of the drug over an extended time period, it would be desirable to be able to deliver a therapeutically effective amount of metronidazole in a once daily dose.
Effectively maintaining acceptable bioavailability of metronidazole for up to 24 hours with a single dose and without increased side effects relative to the conventional multiple dose regimen cannot be accomplished simply by increasing the amount of active drug in a single dose. Metronidazole is aqueous soluble and is rapidly absorbed by the bloodstream. Metronidazole is also rapidly cleared from the bloodstream. Thus, merely administering increased amounts of immediate-release metronidazole results in a rapid peak, followed by a rapid decline in metronidazole levels. Such a profile is undesirable because of side effects caused by high peak levels of metronidazole. Also, the rapid clearing of the drug does not permit plasma metronidazole to remain at acceptable levels for 24 hours.
On the other hand, adding amounts of excipients in ratios typical of conventional modified release formulations which are presently available would result in a tablet which is too large for oral administration. For example, 750 mg of metronidazole represents at least about a 2-fold greater amount of active ingredient than is presently available in other pharmaceutical compositions which are available in modified release form. Moreover, metronidazole itself is not readily compressible, which presents a significant problem with respect to forming modified release tablets.
Thus, there is a need to be able to provide a modified release metronidazole composition which is capable of delivering acceptable bioavailability for up to 24 hours. The composition should be readily compressible such that the entire dose may be provided in a single tablet suitable for oral administration. In order to keep the size of a single tablet in the range of about 1000-1100 mg, while providing about 750 mg of metronidazole, a minor amount of excipient (less than about 30% by weight) must be capable of imparting both compressibility properties (for tabletting) and modified release properties (for bioavailability). Heretofore, there has not been a modified release oral tablet dosage of metronidazole which is suitable for once daily dosing, even though metronidazole has been an accepted therapeutic treatment for trichomoniasis for over 25 years.